rs118204101

Variant names:

• chr11-119091413-C-T
• rs118204101
• NM_000190.4:c.499C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-119091413-C-T
• chr11-119091413-C-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 20P and 4B. PS3 PM1 PM5 PP3_Strong PP5_Very_Strong BS2

The NM_000190.4(HMBS):​c.499C>T​(p.Arg167Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,398,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000577609: Published functional studies demonstrate a damaging effect on enzyme kinetics, resulting in 1-5% of normal enzyme activity and leading to an accumulation of porphyrin precursors (Bustad et al., 2013" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: HMBS NM_000190.4 missense, splice_region
• Scores: Splicing: ADA: 0.3266
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.50
• Publications: 27 publications found

Genes affected

HMBS (HGNC:4982): (hydroxymethylbilane synthase) This gene encodes a member of the hydroxymethylbilane synthase superfamily. The encoded protein is the third enzyme of the heme biosynthetic pathway and catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane. Mutations in this gene are associated with the autosomal dominant disease acute intermittent porphyria. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

HMBS Gene-Disease associations (from GenCC):

• acute intermittent porphyria

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000577609: Published functional studies demonstrate a damaging effect on enzyme kinetics, resulting in 1-5% of normal enzyme activity and leading to an accumulation of porphyrin precursors (Bustad et al., 2013; Solis et al., 2004; Chen et al., 2016).; SCV000944323: Experimental studies have shown that this missense change affects HMBS function (PMID: 1496994, 11055586, 23815679, 27539938).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000190.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-119091414-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1457.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-119091413-C-T is Pathogenic according to our data. Variant chr11-119091413-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 25 AD,SD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000190.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	NM_000190.4	MANE Select	c.499C>T	p.Arg167Trp	missense splice_region	Exon 9 of 14	NP_000181.2
	HMBS	NM_001425056.1		c.499C>T	p.Arg167Trp	missense splice_region	Exon 9 of 14	NP_001411985.1
	HMBS	NM_001425057.1		c.481C>T	p.Arg161Trp	missense splice_region	Exon 9 of 14	NP_001411986.1	A0A3F2YNY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMBS	ENST00000652429.1	MANE Select	c.499C>T	p.Arg167Trp	missense splice_region	Exon 9 of 14	ENSP00000498786.1	P08397-1
	HMBS	ENST00000392841.1	TSL:1	c.448C>T	p.Arg150Trp	missense splice_region	Exon 9 of 14	ENSP00000376584.1	P08397-2
	HMBS	ENST00000545621.5	TSL:1	n.*394C>T		splice_region non_coding_transcript_exon	Exon 9 of 10	ENSP00000444849.1	F5H4X2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000384 AC: 6 AN: 156320 AF XY: 0.0000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000195

Gnomad NFE exome AF: 0.0000331

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 25 AN: 1398000 Hom.: 0 Cov.: 30 AF XY: 0.0000145 AC XY: 10 AN XY: 689650

African (AFR) AF: 0.00 AC: 0 AN: 31572

American (AMR) AF: 0.0000280 AC: 1 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79216

European-Finnish (FIN) AF: 0.000122 AC: 6 AN: 49256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1077708

Other (OTH) AF: 0.0000690 AC: 4 AN: 57944

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000133 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000216 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Acute intermittent porphyria (3)
2	-	-	not provided (2)
1	-	-	Encephalopathy, porphyria-related (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		2.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Loss of disorder (P = 0.005)
MVP		0.99
MPC		0.75
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.33
dbscSNV1_RF	Benign	0.37
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs118204101; hg19: chr11-118962123;